Methods of treating Syndrome X with aliphatic polyamines

a technology of aliphatic polyamine and syndrome x, which is applied in the direction of antinoxious agents, extracellular fluid disorders, metabolic disorders, etc., can solve the problems of increased risk of peripheral vascular and coronary artery disease in individuals with syndrome x, and achieve the effects of improving the symptoms of patients, reducing the ldl level, and raising the plasma level of high density lipoprotein

Inactive Publication Date: 2007-08-28
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0063]A polymer of the invention is administered to a patient in a therapeutically effective amount. As used herein, the terms “therapeutically effective amount” and “therapeutically effective dose” have the same meaning and refer to the amount of an active agent, for example, a therapeutically effective substance, such as a polymer of the invention, required to be administered in order to induce a desired result in the patient. That result may be alleviation or amelioration (complete or partial) of the symptoms of Syndrome X or of the condition of the patient in need of treatment, any other desired improvement in the patient's symptoms, disease or condition, or prophylaxis or delay in the onset of symptoms of Syndrome X.
[0064]As used herein, the term “therapeutically effective amount” may also refer to the quantity of active agent or therapeutically effective substance, such as an amine polymer of the invention, the administration of which results in improvement in the patient's symptoms, disease, or condition, where little or no improvement would occur in the absence of the active agent. Typically, the polymer is administered for a sufficient period of time to achieve the desired therapeutic effect.
[0065]Therapeutic efficacy may be determined by using standard pharmacological procedures in experimental animals.
[0066]For example, the term “therapeutically effective amount” is intended to mean an amount of a composition of the invention that will elevate an individual's plasma HDL level and decrease the LDL level in comparis...

Problems solved by technology

Individuals with Syndrome X have an increased risk of peripheral vascular and coronary artery disease.
Low H...

Method used

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  • Methods of treating Syndrome X with aliphatic polyamines
  • Methods of treating Syndrome X with aliphatic polyamines
  • Methods of treating Syndrome X with aliphatic polyamines

Examples

Experimental program
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Effect test

example 1

Preparation of Poly(allylamine) Hydrochloride

[0082]To a 2 liter, water-jacketed reaction kettle equipped with (1) a condenser topped with a nitrogen gas inlet, (2) a thermometer, and (3) a mechanical stirrer was added concentrated hydrochloric acid (360 mL). The acid was cooled to 5° C. using circulating water in the jacket of the reaction kettle (water temperature=0° C.). Allylamine (328.5 mL, 250 g) was added dropwise with stirring while maintaining the reaction temperature between about 5° C. and about 10° C. After addition was complete, the mixture was removed, placed in a 3 liter one-neck flask, and 206 g of liquid was removed by rotary vacuum evaporation at 60° C. Water (20 mL) was then added and the liquid was returned to the reaction kettle. Azobis(amidinopropane) dihydrochloride (0.5 g) suspended in 11 mL of water was then added. The resulting reaction mixture was heated to about 50° C. under a nitrogen atmosphere with stirring for 24 hours. Additional azobis(amidinopropane...

example 2

Preparation of Poly(allylamine) Hydrochloride Cross-linked with Epichlorohydrin

[0084]To a 5 gallon vessel was added poly(allylamine) hydrochloride prepared as described in Example 1 (1 kg) and water (4 L). The mixture was stirred to dissolve the hydrochloride and the pH was adjusted by adding solid NaOH (284 g). The resulting solution was cooled to room temperature, after which epichlorohydrin cross-linking agent (50 mL) was added all at once with stirring. The resulting mixture was stirred gently until it gelled (about 35 minutes). The cross-linking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and placed in portions in a blender with a total of 10 L of water. Each portion was blended gently for about 3 minutes to form coarse particles which were then stirred for 1 hour and collected by filtration. The solid was rinsed three times by suspending it in water (10 L, 15 L, 20 L), stirring each suspension for 1 ho...

example 3

Alkylation of Poly(allylamine) Cross-linked with epichlorohydrin with (6-Bromohexyl)trimethylammonium bromide and 1-bromodecane alkylating Agent

[0085]To a 12-1 round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser was added methanol (5 L) and sodium hydroxide (133.7 g). The mixture was stirred until the solid dissolved. Cross-linked poly(allylamine) (297 g, ground to −80 mesh size) was added along with additional methanol (3 L). (6-Bromohexyl) trimethylammonium bromide (522.1 g) and 1-bromodecane (311.7 g) were added and the mixture heated to 65° C. with stirring. After 18 hours at 65° C. the mixture was allowed to cool to room temperature. The solid was filtered off and rinsed by suspending, stirring for 30 minutes, and filtering off the solid from: methanol, 12 L; methanol, 12 L; 2 M aqueous NaCl, 22 L; 2 M aqueous NaCl, 22 L; deionized water, 22 L; deionized water, 22 L; deionized water, 22 L and isopropanol, 22 L. The solid was dried in a vacuum o...

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Abstract

The invention relates to a method for treating Syndrome X, or inhibiting the onset of symptoms of Syndrome X in a patient, and includes administering a therapeutically effective amount of a salt of at least one alkylated and cross-linked polymer, or a copolymer thereof, the polymer salt formed as a product of the reaction of one or more polymers, or salts and copolymers thereof, having a repeat unit that is essentially:
where n is a positive integer and each R, independently, is H or a C1–C8 alkyl group; at least one aliphatic alkylating agent; and a cross-linking agent. Long term administration of the cross-linked polyamine salts of the invention increases HDL levels and decreases LDL levels in patients. The invention also provides for administration of the polymer salt colesevelam, in combination with an HMG-CoA reductase inhibitor; the combined administration is effective in further lowering serum total-cholesterol and LDL-cholesterol levels beyond that achieved by either agent alone.

Description

RELATED APPLICATION(S)[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 284,445, filed on Apr. 18, 2001 and U.S. Provisional Application No. 60 / 355,917, filed Feb. 11, 2002. The entire teachings of the above application(s) are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Syndrome X is a combination of metabolic disorders that typically include elevated triglycerides (TG), elevated glycemia, decreased high density lipoprotein cholesterol (HDL), insulin resistance, hyperinsulinemia, high blood pressure, increased plasma uric acid levels, and central body obesity. Individuals with Syndrome X have an increased risk of peripheral vascular and coronary artery disease. Research has shown that individuals who are insulin resistant and hyperinsulinemic are more likely to develop glucose intolerance, hypertension, and hyperlipidemia, characterized by high plasma TG and low HDL levels. Low HDL levels, insulin resistance, and hypertension are ...

Claims

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Application Information

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IPC IPC(8): A61K31/74A61K31/785A61K31/015A61K45/00A61K31/355A61K31/375A61K31/4415A61K31/616A61K31/714A61K45/06A61P3/00A61P39/00
CPCA61K31/015A61K31/355A61K31/375A61K31/4415A61K31/714A61K31/785A61K2300/00A61P3/00A61P39/00A61K31/765A61P3/12A61P7/00A61P7/08A61P13/12A61P43/00
Inventor BURKE, STEVEN K.DONOVAN, JOANNE M.
Owner GENZYME CORP
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